144P - Discovery of CBO421, a first-in-class Drug Fc-Conjugate (DFC), targeting CD73 in Cancer

Background

CD73 (NT5E) contributes to immune evasion in solid tumors by producing immuno-suppressive adenosine. Herein, we describe CBO421, a CD73 targeting DFC, that is a multivalent conjugate of a novel small molecule inhibitor stably linked to a proprietary immune-silent human IgG1 Fc. CBO421 combines the strengths of small molecule inhibitors and monoclonal antibodies (mAbs) targeting CD73 that are in clinical development, with potential best-in-class activity.

Methods

CD73 inhibition was evaluated, and functional activity measured in a PBMC rescue assay with AMP. Binding to cancer cells and CD73 internalization was measured by flow cytometry. Tumor spheroid penetration was measured with CD73⁺ cancer cells. Efficacy of CBO421 was evaluated in syngeneic mouse models.

Results

CBO421 is a potent, AMP-competitive inhibitor of CD73. CD73 inhibition by CBO421 was comparable or superior to small molecules and anti-CD73 mAbs. Unlike most anti-CD73 mAbs, CBO421 demonstrated complete CD73 enzyme inhibition. CBO421 demonstrated potent reactivation of CD8⁺ T cells as measured by CD25⁺ and granzyme B⁺, that was comparable to small molecules and significantly more potent than anti-CD73 mAbs. Differentiated from small molecules, CBO421 triggered CD73 internalization as a second mechanism to reduce CD73 mediated adenosine production. The 2.3-fold smaller size and hydrodynamic radius of CBO421 compared to mAbs significantly improved tumor spheroid penetration. CBO421 demonstrated significant tumor growth inhibition (TGI) in multiple syngeneic mouse models with CD73^- or CD73⁺ cancer cells. Combination therapy of CBO421 with an anti-PD-1 mAb resulted in significant increases in TGI and complete responses when compared with the respective monotherapy. Immunologic memory was demonstrated in complete responders by rejection of tumor upon re-challenge.

Conclusions

CBO421 demonstrated high potency, combined with multiple, distinct mechanisms of action that translated to potent antitumor activity as a monotherapy in syngeneic mouse models that was further improved in combination with PD-1 therapy. Based on these results and other emerging data, CBO421 is being advanced as a clinical development candidate for the treatment of solid cancers.

Legal entity responsible for the study

Cidara Therapeutics, Inc.

Funding

Cidara Therapeutics, Inc.

Disclosure

S. Döhrmann, J. Levin, N. Dedeic, A. Almaguer, D. Zuill, E. Abelovski, M. Hernandez, K. Amundson, M. Moniz, D. Panickar, T. Lam, T. Brady, A. Borchardt, J.N. Cole: Financial Interests, Personal, Full or part-time Employment: Cidara Therapeutics, Inc. Q. Zhao, H. Chen: Financial Interests, Personal, Advisory Board: Cidara Therapeutics, Inc. L.W. Tari: Financial Interests, Personal, Leadership Role: Cidara Therapeutics, Inc.